EKOS endovascular technology facilitates ultrasound-assisted catheter directed thrombolytic [CDT] therapy. The EkoSonicTM system is well characterized for use in CDT therapy for enhancing drug transport into peripheral clots. The EKOS Endovascular system is FDA approved for delivery of physician specified fluids in peripheral and pulmonary vasculature. It has been used with various drugs, including rt-PA, for catheter-directed thrombolysis of Deep Vein Thrombosis (DVT) and Massive Acute Pulmonary Embolism (PE). Chamsuddin et al. (2008) treated 10 patients with 13 massive acute PE lesions with EKOS endovascular systems specifically designed for peripheral vasculature. The mean time of thrombolysis was 24.76 hours 1 8.44 (median, 24 hours) and mean dose of t-PA used was 0.88 mg/h 1 0.19 (13 lesions). No hemorrhagic complications were suffered by any subject. The average total dose of rt-PA used was 21.12mg, 78% less than the fixed 100mg dose of t-PA used in IV thrombolytic administration. Clinical efficacy of intra-arterially delivered ultrasound is determined by ultrasound transducer performance with respect to the target anatomy. Since pulmonary arteries are many times larger than peripheral arteries, we propose to adapt this technology for an effective treatment of massive PE. High power catheter transducers can produce effectual acoustic pressures across the massive pulmonary embolus. Current EKOS' catheter transducers have been designed and tested for power output, longevity, efficiency and efficacy with the intended application in peripheral blood vessels (~6 to 12mm diameter). Hence current transducers are constrained by a very low tolerance when driven at high powers resulting in premature brittle failures. For enhanced drug transport across the transverse cross section of the relatively large pulmonary arteries (~27 mm diameter), the catheter transducers need to have operational ability to be driven at higher acoustic pressures. The overall goal of this project is to develop high power transducers and demonstrate feasibility of ultrasound-assisted thrombolytic therapy using high power catheter transducers to enable improved thrombus removal in massive pulmonary embolism at significantly shortened therapy time in vivo. Lytic drug (rt-PA, Activase(R)) will be infused directly in the immediate clot volume surrounding the high power catheter transducers. Our specific aims are: v SPECIFIC AIM #1: Acoustic characterization of fabricated high power transducer prototypes. We will fabricate transducer prototypes by investigating piezoelectric ceramic fabrication processes to build robust transducers that will have the operational ability to withstand a high electrical input and generate higher acoustic pressures to enhance drug transport across the transverse cross section of the relatively large pulmonary arteries (~27 mm diameter). We will determine the acoustic characteristics of the prototype trasnducers and prevent any unanticipated cavitation activity at the target acoustic pressures via empirical measurements. v SPECIFIC AIM #2: Optimize blood clot formation and conduct bioefficacy and hemolysis evaluation in vitro. To ascertain comparability of in-vitro and in-vivo clots with clinical clots, two independent approaches will be taken to form stasis whole blood clots with similar mechanical and structural property as venous clots (Cortran et al., 1994). The clot formulations will be evaluated by comparing their microstructure, mechanical property and lysis response to reported clinical clot values. The transducer developed in Task 1 will be integrated with its drug infusion catheter and evaluated for efficacy in a well-characterized in-vitro human blood clot perfusion system using both aforementioned clot formulations. Additionally, the hemolytic effect of the acoustic field emitted by this high power transducer will be determined. v SPECIFIC AIM #3: Explore bioefficacy in an in-vivo model of pulmonary embolism using high power transducer incorporated catheter system prototypes. The high power transducer incorporated catheter system prototypes will be tested for bioefficacy in-vivo in a canine model of pulmonary embolism. An autologous clot, formed based on one of the clot formulation in Aim 2, will be formed in a canine pulmonary artery. rt-PA will be delivered into the clot systemically and ultrasound exposure will be administered using catheter systems with high power transducers. At the end of therapy, time to lysis determined angiographically will be used to determine bioefficacy.